tbuckley/cabot-search huggingface dataset:
The impact of treatment adherence on overall survival in non-metastatic colorectal cancer in Latin American patients.
Authors: Fernando Namuche, Jorge Leon, Claudio J. Flores
Journal: Journal of Clinical Oncology (2023)

e15644 Background: Colorectal cancer is a significant public health issue in Peru, and non-metastatic colorectal cancer patients face numerous treatment challenges. Adherence to treatment protocols has been identified as an important factor influencing patient outcomes. However, little is known about the impact of treatment adherence on overall survival in non-metastatic colorectal cancer patients in Peru. The objective of this study is to investigate the association between treatment adherence and overall survival in this patient population. Methods: We retrospectively reviewed the electronic medical files of 890 patients with non metastatic colorectal cancer between 2006 and 2020. Patients were included if they received treatment and were followed up for at least two years. Treatment adherence was measured based on the number of completed chemotherapy cycles and the time to initiate treatment after surgery. Overall survival was defined as the time from diagnosis to death or the last follow-up visit. Multivariate analysis was performed to identify factors associated with overall survival. Results: A total of 890 patients were included in the study, and the median follow-up time was 32 months. The overall adherence rate was 71.7%. Patients who adhered to treatment had a significantly higher overall survival rate compared to non-adherent patients (p &lt; 0.001). A multivariate analysis was performed using Cox regression model with the statistically significant variables found (sex, high histologic grade, stage and adherence to treatment) in the univariate analysis. Multivariate analysis showed that treatment adherence was an independent predictor of overall survival (HR = 0.69; 95% CI, 0.54-0.88; p &lt; 0.001). Conclusions: Our findings indicate that medication adherence is a crucial factor affecting overall survival in Peruvian patients with non-metastatic colorectal cancer. Patients who adhered to treatment had a significantly higher overall survival rate than non-adherent patients, highlighting the importance of adherence in optimizing patient outcomes. These findings have important clinical implications for healthcare providers, who should prioritize efforts to improve treatment adherence in this patient population.
Targeting HE4 for treatment of endometrial cancer using a novel small molecule inhibitor.
Authors: Alexandra Morell, John Miller, Naixin Zhang, Cameron Snyder, Negar Khazan, Myla S. Strawderman, Rakesh Singh, Kyu Kwang Kim, Rachael Turner, Richard G. Moore
Journal: Journal of Clinical Oncology (2023)

e17616 Background: HE4 expression is upregulated in endometrial cancer and has been shown to have prognostic significance in endometrial cancer patients. High-throughput screening and lead optimization led us to discover UR-238, a novel small molecule inhibitor of HE4. The purpose of this study was to investigate the in vitro and in vivo effects of UR-238 in treatment of endometrial cancer. Methods: UR-238 was identified by focused medicinal chemistry. Six endometrial cancer cell lines (ECC1, AN3CA, HEC1A, MFE296, MFE280, and KLE) were grown in cell culture and treated with 8 concentrations of UR-238 (125 nM, 250 nM, 375 nM, 500 nM, 625 nM, 750 nM, 875 nM, and 1000 nM) or DMSO (control). Cell proliferation was assessed using SRB assays at 24 and 48 hours. Effects of UR-238 on the cell cycle were assessed by flow cytometry and related cell-cycle proteins were targeted via Western blots. An ELISA was performed to evaluate UR-238 treatment effect on HE4 expression. An AN3CA xenograft mouse model was used to assess in vivo effects of UR-238. Mice were treated with vehicle control or UR-238 (5 mg/kg, IP, 3 days/week) for 20 days (N=5/group). Tumor volume and weight were evaluated over time using a repeated measures ANOVA. Results: UR-238 resulted in decreased cell proliferation in a dose-dependent manner in all 6 endometrial cancer cell lines. UR-238 increased expression of p21 and p27 and induced M/G2 cell cycle arrest. UR-238 also downregulated HE4 expression. In vivo treatment with UR-238 of AN3CA expressing xenograft mice caused a significant reduction (p=0.02) in mean tumor volume compared with vehicle control after 20 days (control mean 1068.13 mm 3 , SE 239.76; UR-238 mean 265.62 mm 3 , SE 68.82). Conclusions: UR-238 inhibits cell proliferation in endometrial cancer cell lines and exhibits antitumorigenic effects in xenograft mouse models. Future studies are warranted as UR-238 may be a promising therapeutic agent for treatment of endometrial cancer.
Effect of personalized immunization with GNOS-PV02 of patients with hepatocellular carcinoma on TCR clonal expansion, tumor infiltration, and vaccine-specific reactivity.
Authors: Renzo Perales, Neil Cooch, Mark Yarchoan, Niranjan Y. Sardesai, Jian Yan
Journal: Journal of Clinical Oncology (2023)

2629 Background: Tumor-specific neoantigens can be identified from cancer biopsies and used to develop personalized therapeutic cancer vaccines (PTCV) to prime neoantigen-specific T cell responses. Here, we characterized the antitumor neoantigen-specific reactivity of tumor-infiltrating, high-frequency TCR clones in a patient treated with personalized therapeutic DNA cancer vaccine GNOS-PV02 in the ongoing GT-30 advanced hepatocellular carcinoma single-arm open-label multi-center phase Ib/IIa trial (NCT04251117). Methods: Paired blood and tumor biopsy samples from patient #8 enrolled in the GT-30 study were collected before and after treatment with GNOS-PV02 (1mg) + plasmid-encoded IL-12 (0.3mg) + Pembrolizumab (200mg). GNOS-PV02 and IL-12 were administered at Q3W for the first 4 doses, then, at Q9W. Pembrolizumab was administered Q3W. Neoantigen positivity was evaluated by IFNγ-ELISpot. TCRβ sequencing was performed on all 4 samples and single-cell TCR and transcriptome sequencing was performed from T cells isolated from the post-treatment blood sample. After vaccination, three newly identified TCRs in blood and tumor were inserted into a pMXs-IRES-GFP retroviral plasmid vector and used to generate engineered TCR T cells. Engineered T cells were tested against the neoantigens included in PTCV by flow cytometry. Results: The treatment resulted in a partial response with a decrease in tumor size of 44% by RECIST1.1. Five vaccine-encoded responding neoantigens were identified. Differential abundance frame network analysis revealed that 27 of 42 (64.28%) significantly expanded peripheral TCR clones were also found enriched in the tumors post-treatment. Importantly, we observed an increase in cumulative frequency (from 0.4 to 7.7%), and absolute numbers (from 3 to 14) of significantly expanded vaccine-specific TCR clones in the tumor. Increased TCR clonality confirmed a focused tumor repertoire response. Single-cell sequencing data analysis revealed that the 6 most expanded clones in blood were activated CD8+CD69+ T cells (81.82%). Three full TCR sequences from T cell clones newly present in the tumor post-vaccination were selected, synthesized and cloned. TCR-engineered patient-specific T cells showed a dose-dependent CD8+ and CD4+ T cell activation (CD69+) upon stimulation with a pool of epitopes covering all the neoantigens in the patient’s PTCV. Conclusions: PTCV treatment resulted in neoantigen-specific T cell responses, clonal expansion in the periphery and primary lesion, and tumor infiltration of T cells with an activated phenotype. TCR-engineered high-frequency T cells found in the tumor are reactive to PTCV-encoded neoantigens post-treatment. These results may account for the observed objective decrease in the primary tumor size.
When to treat: A multicenter retrospective study of timing of radiation therapy in 1p19q co-deleted, IDH mutated oligodendrogliomas.
Authors: Isabella Densmore, Tyler Ashford Lanman, Tresa McGranahan
Journal: Journal of Clinical Oncology (2023)

e14036 Background: Oligodendrogliomas, molecularly defined by IDH mutation and 1p19q codeletion, have a protracted natural history and are more chemoresponsive compared to astrocytomas. While the addition of chemotherapy to radiation improves survival, if chemoradiation should be initiated following diagnosis or at progression remains unknown. Given the potential for early and late radiation-related toxicity, a careful evaluation of timing of treatment is critical to optimize treatment guidelines for oligodendroglioma. We aimed to evaluate the benefit of initial adjuvant radiation therapy (RT) on survival in patients with oligodendrogliomas. Methods: We conducted a multicenter retrospective study of patients treated at the University of Washington and Stanford Medical Center with oligodendrogliomas using both 1p19q codeletion and IDH mutation to define the diagnosis, reflecting the World Health Organization 2021 diagnostic criteria. Survival probability, overall survival (OS) and time to first progression (PFS), were calculated using Kaplan-Meier method with distributions compared using log-rank test in GraphPad Prism. Propensity Score Matching was completed using XLSTAT. Results: 243 patients were identified as oligodendroglioma and 229 had treatment and survival data available with a median follow up of 5.8 years(y). Median OS was 22.5y and median PFS was 5.35y. 110 patients were treated with adjuvant radiation (aRT) within 1y of diagnosis and 119 underwent observation or chemotherapy alone (delayed RT, or dRT). PFS was comparable between aRT (7.7y) and dRT (4.6y) but OS was longer in dRT (27.8y) than aRT (13.7y) (p &lt; 0.001). Given imbalance in baseline characteristics, propensity score matching was used to adjust for high risk factors of age, grade and presence of residual disease resulting in 63 pairs. In this matched cohort, aRT prolonged PFS (aRT = 7.75y v. dRT = 4.33y, p = 0.006) however dRT still demonstrated a survival benefit (p = 0.017). 59 dRT patients were treated with RT at progression and also had longer medan OS of 22.6y compared to 13.7y in the aRT (p = &lt; 0.0001). The time to RT for this cohort ranged be 1.1-19y. Conclusions: To our knowledge this is the largest retrospective study of molecularly defined oligodendrogliomas that includes treatment information. This study confirms the protracted natural history of this disease. In our multi-institution cohort, early adjuvant radiation therapy may increase PFS but was not found to prolong OS. Prospective studies evaluating the timing of treatment in patients with oligodendroglioma are needed. [Table: see text]
Timing of immunotherapy-induced pneumonitis in patients with primary lung malignancy.
Authors: Megan Winter, Madiha Atif Gilani, Manasa Anipindi, Tejaswi Venigalla, Shriya Doreswamy
Journal: Journal of Clinical Oncology (2023)

2647 Background: Pneumonitis is a widely recognized side effect of immunotherapy with increased incidence in non-small cell lung cancers as compared to other solid organ malignancies. A review of the literature demonstrates an incidence of 5% in patients receiving PD-1/PD-L1 inhibitors. While biopsy provides definitive diagnosis of immunotherapy-induced pneumonitis, clinical symptoms and radiologic features are most utilized with treatment guided by the grade of toxicity. The ability to predict the timing, which patients, and to what extent pneumonitis will present has been a significant challenge. Our study aims to look at the timing of onset of immunotherapy-induced pneumonitis in patients treated with checkpoint inhibitors for primary lung cancer to elicit patterns which may assist in diagnosis and appropriate treatment. Methods: This is a single-institution, retrospective study reviewing patients with primary lung cancer who received checkpoint inhibitors between January 2018 and January 2023. The focus was on the date of initiation of therapy and the date of onset of pneumonitis. Immunotherapy-induced pneumonitis was defined as development of abnormal imaging findings with or without respiratory symptoms following initiation of immunotherapy and graded by the Common Terminology Criteria for Adverse Events (CTCAE). Additional patient demographics were collected to assess secondary patterns. Results: A total of 117 patients met the specified search criteria. Of these, 10 patients (8.5%) met the criteria for immunotherapy-induced pneumonitis. The average time between receiving the first dose of immunotherapy and the development of immunotherapy-induced pneumonitis was 66.5 days (range of 1 to 163 days). The average number of cycles received before diagnosis was 3.7, with most cases occurring after less than 5 cycles provided (7 out of 10). The grade of pneumonitis ranged from 1 to 5. All patients had non-small cell lung cancer, with the most prevalent histology being squamous cell carcinoma, ranging from stage III to stage IV. Durvalumab was the most prevalent immunotherapy (6 of the 10). Conclusions: The timing of immunotherapy-induced pneumonitis, while variable, occurred after receiving less than 5 cycles in majority of our cases, with most occurring after just 1 cycle. Interestingly, durvalumab was the most common immunotherapy in these cases. While our study is limited by the number of patients, the incidence of pneumonitis in our study was close to that of the national average and may, also, be reflective of the timing of immunotherapy-induced pneumonitis. Additional studies with larger numbers of patients are needed.
Comprehensive genomic profiling and therapeutic implications for patients with advanced cancers: The experience of an academic hospital.
Authors: Laure-Anne Marie Nicole Teuwen, Evelyne Roets, Pieter D'Hoore, Patrick Pauwels, Hans Prenen
Journal: Journal of Clinical Oncology (2023)

e15162 Background: Next generation sequencing (NGS) can be used to detect tumor-specific genomic alterations, with the aim to identify actionable genomic alteration and provide additional treatment options for patients with advanced cancer. While smaller sequencing panels are being applied broadly, controversy exists around the routine implementation of comprehensive genomic profiling with large multigene NGS panels. Indeed, there is an ongoing discussion about the indications as well as timing of comprehensive genomic profiling in patients with advanced solid tumors. Therefore, there is a need for more data to increase understanding of the potential indications and added clinical benefit of routine implementation of broad comprehensive genomic profiling. However, available studies have often been reporting on a small patient population, which complicates the interpretation and translation to the clinical setting. This study aims to describe the feasibility of performing broad NGS panels in patients with advanced cancer in an academic hospital setting, as well as the targetable alterations detected. Methods: In this retrospective study, we analysed genomic alterations in solid tumor biopsies of 464 patients with locally advanced or metastatic cancer. Next generation sequencing was performed using the Foundation Medicine assay (FoundationOneCDx). The therapeutic implications of the genomic alterations were determined using the OncoKB classification. Results: The FoundationOne CDx was successfully applied in 464/521 patients (89%) with a range of cancer types. The most common altered genes were TP53 (61%), followed by KRAS (20%), CDKN2A (20%), TERT (16%), APC (16%), PTEN (14%), PIK3CA (14%) and CDKN2B (14%). Among 419 patients with successfully analyzed tumor mutational burden (TMB), the median TMB was 2.52 (range 0 – 67) mutations/Mb (mut/Mb). Forty-three patients presented with a high-TMB ( &gt; = 10 mut/Mb) of which eight had microsatellite instability. Out of 126 patients with an actionable target (e.g. ERBB2, KRAS, PIK3CA, FGFR2), 40 patients received matched treatment (8.6%), of which 17 were included in clinical trials. Conclusions: This single-center retrospective study shows that broad application of NGS is feasible in an academic center, increases the detection of actionable genomic alterations, and opens opportunities to provide treatment with immune checkpoint inhibitors in case of high tumor mutational burden and microsatellite instability status regardless of tumor histology. The study brings to attention that strategies such as inclusion in clinical (basket) trials and development of new targeted drugs are necessary to improve matched treatment rates. Further research is needed to assess the possible clinical benefit of broad application of NGS and genotype matched treatment.
Randomized phase 2 study of maintenance olaparib vs olaparib plus durvalumab for DNA damage repair (DDR) gene mutated unresectable or metastatic biliary tract cancer (BTC) with durable response to first-line platinum-based chemotherapy: OPTIMUM trial.
Authors: YunJung Kim, Boram Ok, Inkeun Park, Baek-Yeol Ryoo, Kyu-Pyo Kim, Changhoon Yoo
Journal: Journal of Clinical Oncology (2023)

TPS4180 Background: BTC is rare and aggressive disease with heterogeneous genetic profiles. Gemcitabine plus cisplatin (GemCis) with or without durvalumab is the standard first-line therapy but further improvement in survival outcomes is needed. In a prior study (Chae HJ et al, Eur J Cancer 2019), germline or somatic mutations in DDR genes including BRCA are detected more than half of BTC patients and associated with better survival outcomes with platinum-based chemotherapy. As the potential efficacy of Olaparib in DDR-mutated cancers and synergism between PARP inhibitors and immune checkpoint inhibitors, we designed randomized phase 2 trial investigating the efficacy and safety of olaparib monotherapy vs olaparib plus durvalumab in BTC patients as maintenance therapy for BTC patients who showed durable response to first-line platinum-based chemotherapy. Methods: This is a randomized, open-label phase 2 study conducted in a single center (Asan Medical Center, Seoul, Korea). Key eligibility criteria include histologically documented locally advanced unresectable or metastatic BTC, no progression at least 16 weeks with first-line platinum-based chemotherapy, DDR mutations on targeted sequencing of tumor tissues and ctDNA, ECOG performance status 0–1, and adequate organ function. Eligible patients will be randomized 1:1 into olaparib monotherapy arm (300 mg twice daily, every 4 weeks) or olaparib plus durvalumab (1,500 mg intravenous, every 4 weeks) arm. Study treatment is continued until disease progression, unacceptable toxicity, withdrawal of consent, or death. Response evaluation is performed every 8 weeks (fixed). Stratification factors are tumor location (intrahepatic vs extrahepatic/gallbladder) and best response to platinum-based chemotherapy (CR/PR vs SD). The six-month progression-free survival rates are the primary endpoint and overall survival, progression-free survival, response rates, and safety profiles are secondary endpoints. A total of 62 patients (31 for each arm) are planned, and 23 (37%) patients (ATM [n=6], BRCA2 [n=7], CHEK2 [n=2], BRCA1 [n=1], RAD51C [n=1], and PBRM1 [n=1]) are enrolled as of Jan 2023. Clinical trial information: NCT05222971 .
PD-L1 expression as a unique negative predictive biomarker in advanced squamous NSCLC when treated with first-line chemotherapy.
Authors: Nicky Wong Zhun Hong, Joseph J Zhao, Ke Xin Zhu, Dominic Wei Ting Yap, Nesaretnam Barr Kumarakulasinghe, Yiqing Huang, Raghav Sundar
Journal: Journal of Clinical Oncology (2023)

e21140 Background: PD-L1 expression has been established as a positive predictive biomarker for immune checkpoint inhibition in advanced non-small cell lung cancer (NSCLC). We hypothesize that PD-L1 serves as a negative predictive biomarker of chemotherapy in squamous NSCLC in contrast to non-squamous NSCLC. Methods: Phase III randomized trials that investigated PD-L1 expression as a biomarker in advanced squamous NSCLC at first-line were identified and included through a systematic search of Embase and PubMed from inception until 24 th September, 2022. To investigate the anti-thesis, trials that reported PD-L1 stratified KM plots in non-squamous NSCLC were evaluated too. Only trials that reported PD-L1 stratified KM curves of chemotherapy arms were included. A graphical reconstructive algorithm was used to retrieve survival data from reported Kaplan-Meier (KM) curves. Pooled survival analyses for progression-free and overall survival (PFS, OS) were conducted with Cox proportional hazard models with a shared-frailty term incorporated to account for inter-study differences. Results: Five phase III randomized trials (2 squamous NSCLC and 3 non-squamous NSCLC) reporting PD-L1 stratified KM plots of patients treated with first-line chemotherapy were included. In patients with squamous histology, PD-L1 expression negatively predicted for chemotherapy benefit – patients with higher PD-L1 expression were at a higher risk of tumour progression (PD-L1 ≥50% [n = 187] vs PD-L1 &lt; 1% [n = 247]: HR = 1.474, 95%-CI: 1.171-1.855, p &lt; 0.001; PD-L1 ≥50% [n = 187] vs PD-L1 1-49% [n = 239]: HR = 1.300, 95%-CI: 1.033-1.625, p = 0.025). Conversely, in patients with non-squamous histology, no significant differences in tumour progression was shown between PD-L1 subgroups (PD-L1 ≥50% [n = 137] vs PD-L1 &lt; 1% [n = 242]: HR = 1.238, 95%-CI: 0.919-1.667, p = 0.160; PD-L1 ≥50% [n = 137] vs PD-L1 1-49% [n = 199]: HR = 0.958, 95%-CI: 0.714 -1.285, p = 0.780). No significant difference in OS was found between PD-L1 subgroups dichotomized at 1% &amp; 50% among patients with squamous histology. In contrast, in patients with non-squamous histology, PD-L1 was a positive biomarker for chemotherapy benefit – patients with higher PD-L1 were at a lower risk of mortality (PD-L1 ≥50% [n = 40] vs PD-L1 &lt; 1% [n = 150]: HR = 0.523, 95%-CI: 0.316-0.865, p = 0.012). Conclusions: These findings suggest that PD-L1 expression is uniquely a negative predictor for tumour progression in advanced squamous NSCLC treated with first-line chemotherapy.